PROJECT SUMMARY: Linking the chemical structure of an odorant to its percept is a longstanding problem in sensory physiology. It underscores the need to clarify ligand-receptor interactions, especially in terms of how to most meaningfully define a complex chemical stimulus. The challenge of identifying the relevant features of a chemical stimulus is shared by both odorants and drugs. Understanding how the odorant receptors (ORs) of the mammalian peripheral olfactory system functionally classify odorants may thus assist rational drug design, especially among the Class A subtype of G-protein coupled receptors to which the ORs belong. Currently, the functional relationships between odorants are unclear. The relevant dimensions of odorants are not intuitive. While most other primary sensory cortices have ?maps? that reflect regularities in their stimuli, piriform cortex has no clear chemotopic map to serve as a guide as to which odorants are ?proximal? in chemical space. With no other guide, the default organization of odorants has come from organic chemistry. But olfactory paradoxes suggest that this traditional way of categorizing odorants is insufficient. Some percepts, such as musk, can be elicited by highly divergent chemical structures. Yet highly similar chemical structures, such as the enantiomers of carvone, can sometimes elicit markedly non-overlapping percepts. One problem may be that organic chemistry emphasizes those features that impact synthetic reaction schemes. These features may not have the same relevance in a biological setting. A more biologically-relevant classification of odorants is needed. Medicinal chemistry can help provide this new perspective because it emphasizes a compound?s biological function over its chemical form. Some chemical fragment substitutions central to medicinal chemistry generate compounds that appear discrepant and yet these compounds often remain functional at their intended targets, a phenomenon called bioisosterism. We propose to challenge the ability of the diverse ORs to accept three key medicinal chemistry fragment substitutions: exchanging aromatic rings, inverting esters, and bioisosteric substitution of aliphatic scaffolds for a benzene ring. If odorants related by these fragment substitutions elicit similar activity patterns across the OR repertoire, it will support the use of ORs as a naturally diverse platform for drug screening. We will also identify the specific receptors that are activated by the various substitutions in order to develop a new, functionally based, classification of the odor receptor family.